Protective effects of sulforaphane on diabetic retinopathy: activation of the          Nrf2 pathway and inhibition of NLRP3 inflammasome formation

High glucose (HG)-induced Drp1 overexpression contributes to mitochondrial dysfunction and promotes apoptosis in retinal endothelial cells. However, it is unknown whether inhibiting Drp1 overexpression protects against the development of retinal vascular cell loss in diabetes. To investigate whether reduced Drp1 level is protective against diabetes-induced retinal vascular lesions, four groups of mice: wild type (WT) control mice, streptozotocin (STZ)-induced diabetic mice, Drp1+/− mice, and STZ-induced diabetic Drp1+/− mice were examined after 16 weeks of diabetes. Western Blot analysis indicated a significant increase in Drp1 expression in the diabetic retinas compared to those of WT mice; retinas of diabetic Drp1+/− mice showed reduced Drp1 level compared to those of diabetic mice. A significant increase in the number of acellular capillaries (AC) and pericyte loss (PL) was observed in the retinas of diabetic mice compared to those of the WT control mice. Importantly, a significant decrease in the number of AC and PL was observed in retinas of diabetic Drp1+/− mice compared to those of diabetic mice concomitant with increased expression of pro-apoptotic genes, Bax, cleaved PARP, and increased cleaved caspase-3 activity. Preventing diabetes-induced Drp1 overexpression may have protective effects against the development of vascular lesions, characteristic of diabetic retinopathy.

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Analysis of Lipid Peroxidation by UPLC-MS/MS and Retinoprotective Effects of the Natural Polyphenol Pterostilbene

Antioxidants ◽

10.3390/antiox10020168 ◽

2021 ◽

Vol 10 (2) ◽

pp. 168

Author(s):

Isabel Torres-Cuevas ◽

Iván Millán ◽

Miguel Asensi ◽

Máximo Vento ◽

Camille Oger ◽

...

Keyword(s):

Lipid Peroxidation ◽

Diabetic Retinopathy ◽

Redox Homeostasis ◽

Ultra Performance Liquid Chromatography ◽

Protective Effects ◽

Diabetic Retina ◽

Key Factor ◽

Adrenic Acid ◽

Diabetic Rabbits ◽

High Level

The loss of redox homeostasis induced by hyperglycemia is an early sign and key factor in the development of diabetic retinopathy. Due to the high level of long-chain polyunsaturated fatty acids, diabetic retina is highly susceptible to lipid peroxidation, source of pathophysiological alterations in diabetic retinopathy. Previous studies have shown that pterostilbene, a natural antioxidant polyphenol, is an effective therapy against diabetic retinopathy development, although its protective effects on lipid peroxidation are not well known. Plasma, urine and retinas from diabetic rabbits, control and diabetic rabbits treated daily with pterostilbene were analyzed. Lipid peroxidation was evaluated through the determination of derivatives from arachidonic, adrenic and docosahexaenoic acids by ultra-performance liquid chromatography coupled with tandem mass spectrometry. Diabetes increased lipid peroxidation in retina, plasma and urine samples and pterostilbene treatment restored control values, showing its ability to prevent early and main alterations in the development of diabetic retinopathy. Through our study, we are able to propose the use of a derivative of adrenic acid, 17(RS)-10-epi-SC-Δ15-11-dihomo-IsoF, for the first time, as a suitable biomarker of diabetic retinopathy in plasmas or urine.

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Protective Effects ofPanax notoginsengSaponins against High Glucose-Induced Oxidative Injury in Rat Retinal Capillary Endothelial Cells

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2016/5326382 ◽

2016 ◽

Vol 2016 ◽

pp. 1-9 ◽

Cited By ~ 19

Author(s):

Yue Fan ◽

Yuan Qiao ◽

Jianmei Huang ◽

Minke Tang

Keyword(s):

Endothelial Cells ◽

Diabetic Retinopathy ◽

High Glucose ◽

Microvascular Dysfunction ◽

Panax Notoginseng ◽

Protective Effects ◽

Pronounced Increase ◽

Nadph Oxidase 4 ◽

Retinal Capillary ◽

Capillary Endothelial Cells

Diabetic retinopathy, a leading cause of visual loss and blindness, is characterized by microvascular dysfunction. Hyperglycemia is considered the major pathogenic factor for diabetic retinopathy and is associated with increased oxidative stress in the retina. In this study, we investigated the potential protective effects ofPanax notoginsengSaponins (PNS) in retinal capillary endothelial cells (RCECs) exposed to high glucose conditions. We found a pronounced increase in cell viability in rat RCECs incubated with both PNS and high glucose (30 mM) for 48 h or 72 h. The increased viability was accompanied by reduced intracellular hydrogen peroxide (H2O2) and superoxide (O2-), decreased mitochondrial reactive oxygen species (ROS), and lowered malondialdehyde (MDA) levels. PNS also increased the activities of total superoxide dismutase (SOD), MnSOD, catalase (CAT), and glutathione peroxidase (GSH-PX). The glutathione (GSH) content also increased after PNS treatment. Furthermore, PNS reduced NADPH oxidase 4 (Nox4) expression. These results indicate that PNS exerts a protective effect against high glucose-induced injury in RCECs, which may be partially attributed to its antioxidative function.

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Key Mechanisms and Potential Implications of Hericium erinaceus in NLRP3 Inflammasome Activation by Reactive Oxygen Species during Alzheimer’s Disease

Antioxidants ◽

10.3390/antiox10111664 ◽

2021 ◽

Vol 10 (11) ◽

pp. 1664

Author(s):

Marika Cordaro ◽

Angela Trovato Salinaro ◽

Rosalba Siracusa ◽

Ramona D’Amico ◽

Daniela Impellizzeri ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Nlrp3 Inflammasome ◽

Neuronal Degeneration ◽

Behavioral Changes ◽

Antioxidant Systems ◽

Inflammasome Activation ◽

Protective Effects ◽

Behavioral Alteration ◽

Hericium Erinaceus

Alzheimer’s disease (AD) is the principal cause of dementia, and its incidence increases with age. Altered antioxidant systems and inflammation have an important role in the etiology of neurodegenerative disorders. In this study, we evaluated the effects of Hericium erinaceus, a nutritional mushroom with important antioxidant effects, in a rat model of AD. Animals were injected with 70 mg/Kg of AlCl3 daily for 6 weeks, and Hericium erinaceus was administered daily by gavage. Before the experiment’s end date, behavioral test training was performed. At the end of the study, behavioral changes were assessed, and the animals were euthanized. Brain tissues were harvested for further analysis. AlCl3 mainly accumulates in the hippocampus, the principal region of the brain involved in memory functions and learning. Hericium erinaceus administration reduced behavioral changes and hippocampal neuronal degeneration. Additionally, it reduced phosphorylated Tau levels, aberrant APP overexpression, and β-amyloid accumulation. Moreover, Hericium erinaceus decreased the pro-oxidative and pro-inflammatory hippocampal alterations induced by AD. In particular, it reduced the activation of the NLRP3 inflammasome components, usually activated by increased oxidative stress during AD. Collectively, our results showed that Hericium erinaceus has protective effects on behavioral alteration and histological modification associated with AD due to the modulation of the oxidative and inflammatory pathways, as well as regulating cellular brain stress.

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Vaspin Alleviates Osteoarthritis by Inhibiting NLRP3-mediated Inflammation

10.21203/rs.3.rs-285169/v1 ◽

2021 ◽

Author(s):

Xianjie Zhu ◽

Shiyou Dai ◽

Baohua Xia ◽

Jianbao Gong ◽

Bingzheng Ma

Keyword(s):

Nlrp3 Inflammasome ◽

Wistar Rat ◽

Cartilage Degradation ◽

Pathological Process ◽

Inflammasome Activation ◽

Protective Effects ◽

Collagen Formation ◽

Nlrp3 Inflammasome Activation

Abstract Background:Osteoarthritis (OA) is a chronic degenerative joint bone disease characterized by cartilage degradation. Visceral adipose tissue-derived serine protease inhibitor (vaspin) is associated with the inflammatory and metabolic responses to OA. However, the underlying mechanisms of the pathological process of OA are not clear. The aim of the present study was to examine the protective effects of vaspin both in vitro and in vivo.Methods:Monosodium iodoacetate (MIA)-induced Wistar rat model of OA was used to assess the in vivo effects of vaspin administered for 12 weeks. The characteristics of OA were evaluated by haematoxylin and eosin (H&E) and safranin O/fast green staining. The anti-inflammatory effect of vaspin was assessed using immunohistochemical, qRT-PCR, and western blotting analysis. Parallel experiments to detect the molecular mechanism through which vaspin prevents OA were performed using LPS-treated chondrocytes.Results:Our results showed that the degeneration of cartilage and upregulated expression of matrix metalloproteinase (MMP)-1 and MMP-13 were ameliorated by vaspin. Additionally, vaspin suppressed the activation of TXNIP/NLRP3 and secretion of tumor necrosis factor ɑ and interleukin-1β in vivo. It was further confirmed that vaspin could also suppress LPS-induced NLRP3 inflammasome activation and reduce collagen formation in chondrocytes. Moreover, vaspin inhibited NLRP3 inflammasome activation by suppressing the ROS/TXNIP pathway.Conclusions: Vaspin inhibited OA by repressing TXNIP/NLRP3 activation in in vitro and in vivo models of OA, thus providing a novel therapeutic strategy for OA.

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Abstract TP97: Korean Red Ginseng Ameliorates Cerebral Hypoxic-Ischemic Damage Through the Activation of the Nrf2 Pathway by Preferentially Altering Reactive Astrogliosis

Stroke ◽

10.1161/str.48.suppl_1.tp97 ◽

2017 ◽

Vol 48 (suppl_1) ◽

Author(s):

Lei Liu ◽

Mary K. Vollmer ◽

Morgan W. Carson ◽

Todd J. Sahagian ◽

Hocheol Kim ◽

...

Keyword(s):

Brain Damage ◽

Neuronal Death ◽

Ischemic Damage ◽

Protective Effects ◽

Red Ginseng ◽

Korean Red Ginseng ◽

Neuroprotective Effects ◽

Edema Formation ◽

Ischemic Brain ◽

Nrf2 Pathway

Introduction: Endogenous defense mechanisms by which the brain protects itself against noxious stimuli and recovers from ischemic damage are key targets of stroke research that may ultimately facilitate functional recovery. Multiple evidences indicate that the transcriptional factor Nrf2 plays a vital role in cellular defense against oxidative stress and inflammation, and consequently, targeting Nrf2 has emerged as a promising therapeutic strategy for disease prevention. Korean Red Ginseng (Ginseng), one of the most widely used herbal medicines in the world, has been suggested as one of the most potent Nrf2 activators, thereby making it efficacious against various acute neurological disorders, including stroke. Hypothesis: To evaluate whether Ginseng could exert protective effects against hypoxic-ischemic brain damage and whether Nrf2 activation is pivotal to the various neuroprotective effects of Ginseng. Methods: C57BL/6 WT and Nrf2 knockout mice (10-18 weeks old, n=12-16) were orally administered Ginseng (100mg/kg/d) or vehicle 7d prior to cerebral hypoxic-ischemic damage. At 6 and 24h after stroke, mice were neurologically scored. Brain lesion size and edema formation were measured at 24h. Using immunostaining, we examined which cells appeared to be most preferentially activated in a spatiotemporal pattern by this Nrf2 pathway, in particular, in the early stage of ischemic injury. Based on the results, we are further evaluating the efficacy of inducing the Nrf2 pathway and assess the extended neuroprotective effects of Ginseng at 7d after stroke. Results: Ginseng treatment significantly reduced cerebral infarct size, neuronal death, edema formation and the resultant functional neurological deficits at 24h after stroke (P<0.001); whereas, Nrf2 ablation remarkably attenuated all benefits. Notably, the above protective effects of Ginseng were significantly attenuated in Nrf2 knockouts (P<0.05). In addition, Ginseng treated mice also exhibited reduced neuronal death and delayed severe reactive astrogliosis at 6 and 12h (P<0.05). Conclusion: Our findings indicate a neuroprotective effect of Ginseng against hypoxic-ischemic brain damage, and that Nrf2-dependent cytoprotective responses appear to be more prominent in astrocytes.

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Exosome derived from mesenchymal stem cells enhance autophagy and inhibit iNOS/TXNIP/NLRP3 inflammasome axis in injured spinal cord

10.21203/rs.3.rs-16805/v1 ◽

2020 ◽

Author(s):

Bin Lv ◽

Lei Wang ◽

Anquan Huang ◽

Tianming Zou ◽

Jishan Yuan

Keyword(s):

Nitric Oxide ◽

Spinal Cord ◽

Nlrp3 Inflammasome ◽

Neuroprotective Effect ◽

Neuronal Cells ◽

Tissue Loss ◽

Protective Effects ◽

Sprague Dawley ◽

Cord Injury

Abstract Background: Neuroinflammation, autophagy, NLRP3 inflammasome, and microglia polarizationhave been implicated in spinal cord injury (SCI).Moreover, exosomes, a classic nanovesicles secreted by MSCs, may have a neuroprotective effect on transformation of microglia from the M1 state to the M2 phenotype. However, the effect of MSCs derived exosomes on neuroinflammation is still unclear. Here, we investigated the mechanisms of MSCs derived exosomes mediated NLRP3 inflammasome signaling cascades and its protective effects in SCI. Methods:The SCI model was performed by weight-drop impact in adult male Sprague-Dawley (SD) rats. Control andexosome rats were randomly subjecttoexosomeadminister (20 mg/kg) or placebo via intraperitoneal route 1 h after SCI.Autophagy inhibitor(3-MA) was administered intraperitoneally 20 min before experiment.Neurological function was measured by Basso-Beattie-Bresnahan (BBB) scoring and an open-field test.Neuronal death was measured by HE stainingandNisslstaining.Inducible nitric oxide synthase (iNOS) levels were determined using fluorescent probes. The autophagy and TXNIP and its downstream signaling pathways-mediated polarization of macrophages/microglia was assessed by immunohistochemistry. Results:Exosome significantly downregulated intracellular iNOS and inhibited TXNIP, pyrin domain-containing 3 (NLRP3) inflammasome pathway activation by activating autophagy. Additionally, Exosomepromoted expression of autophagy markers, such as LC3A/B and beclin1,and abrogated the expression of p62. Autophagy inhibitor, 3-MA, blockage of autophagy flux abolished the inhibition of apoptosis and iNOS/TXNIP/NLRP3 inflammasome axisafterSCI. Here, we demonstrated that exosomeadministration in spinal cord markedly reduced tissue loss, attenuate pathological morphology of the injuredregion, and promoted tissue recovery. Moreover. our resultshowed that exosome administration alleviated neuronal cells apoptosis, and inhibited nitric oxide release in microglia.The activation of inflammatoryresponse in neuronal cells facilitates interactions of iNOS‐NLRP3 andTXNIP‐NLRP3and inhibited NLRP3 inflammasome where neuronal cells apoptosis was induced.Further, we found that exosome could suppress macrophages/microglia polarized to M1 phenotype in vivo and in vitro.Taken together, exosome administration exerts protective effects in neuronal cells through inhibiting iNOS production, and exosome administration could inhibit iNOS/TXNIP/NLRP3 inflammasome axis via enhancing autophagy and both in vitro and in vivo. Conclusions:These resultsreveal that exosometreatment alleviatedneuroinflammation and mitigates neuronal apoptosis via autophagy-mediate inhibition of the iNOS/TXNIP/NLRP3 inflammasome axis. Our findings suggest that exosome may be a novel therapeutic target for treating SCI.

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Notoginsenoside R1 Ameliorates Diabetic Retinopathy through PINK1-Dependent Activation of Mitophagy

Cells ◽

10.3390/cells8030213 ◽

2019 ◽

Vol 8 (3) ◽

pp. 213 ◽

Cited By ~ 15

Author(s):

Ping Zhou ◽

Weijie Xie ◽

Xiangbao Meng ◽

Yadong Zhai ◽

Xi Dong ◽

...

Keyword(s):

Oxidative Stress ◽

Diabetic Retinopathy ◽

Oral Treatment ◽

Müller Cells ◽

Panax Notoginseng ◽

Protective Effects ◽

Muller Cells ◽

Beneficial Effects ◽

Pre Treatment ◽

Lc3 Puncta

: Accumulating evidence has indicated that inflammation, oxidative stress, apoptosis, and autophagy in retinal Müller cells are involved in diabetic retinopathy (DR). Notoginsenoside R1 (NGR1), a novel saponin extracted from Panax notoginseng, posesses pharmacological properties, including treating diabetic encephalopathy and improving microcirculatory disorders. Nevertheless, its beneficial effects on DR and the potential mechanism remain to be elucidated. In this study, we found retinal vascular degeneration, reduced retinal thickness, and impaired retinal function in db/db mice were all dramatically attenuated by oral treatment with NGR1 (30 mg/kg) for 12 weeks. NGR1 pretreatment also significantly inhibited apoptosis, markedly suppressed the VEGF expression, markedly increased PEDF expression and markedly inhibited oxidative stress and inflammation in rat retinal Müller cells (rMC-1) subjected to high glucose (HG) and in the retinas of db/db mice. Furthermore, NGR1 pre-treatment upregulated the level of PINK1 and Parkin, increased the LC3-II/LC3-I ratio, and downregulated the level of p62/SQSTM1 in rMC-1 cells induced by HG and in the retinas of db/db mice. Moreover, NGR1 administration enhanced the co-localization of GFP-LC3 puncta and MitoTracker in rMC-1 cells. Importantly, knockdown of PINK1 abolished the protective effects of NGR1. In conclusion, these phenomena suggested that NGR1 prevented DR via PINK1-dependent enhancement of mitophagy.

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Genetic Deletion or Pharmacological Inhibition of Soluble Epoxide Hydrolase Ameliorates Cardiac Ischemia/Reperfusion Injury by Attenuating NLRP3 Inflammasome Activation

International Journal of Molecular Sciences ◽

10.3390/ijms20143502 ◽

2019 ◽

Vol 20 (14) ◽

pp. 3502 ◽

Cited By ~ 7

Author(s):

Ahmed M. Darwesh ◽

Hedieh Keshavarz-Bahaghighat ◽

K. Lockhart Jamieson ◽

John M. Seubert

Keyword(s):

Nlrp3 Inflammasome ◽

Epoxide Hydrolase ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Soluble Epoxide Hydrolase ◽

Inflammasome Activation ◽

Protective Effects ◽

Isolated Hearts ◽

Pyrin Domain ◽

Cardioprotective Effects

Activation of the nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome cascade has a role in the pathogenesis of ischemia/reperfusion (IR) injury. There is growing evidence indicating cytochrome p450 (CYP450)-derived metabolites of n-3 and n-6 polyunsaturated fatty acids (PUFAs) possess both adverse and protective effects in the heart. CYP-derived epoxy metabolites are rapidly hydrolyzed by the soluble epoxide hydrolase (sEH). The current study hypothesized that the cardioprotective effects of inhibiting sEH involves limiting activation of the NLRP3 inflammasome. Isolated hearts from young wild-type (WT) and sEH null mice were perfused in the Langendorff mode with either vehicle or the specific sEH inhibitor t-AUCB. Improved post-ischemic functional recovery and better mitochondrial respiration were observed in both sEH null hearts or WT hearts perfused with t-AUCB. Inhibition of sEH markedly attenuated the activation of the NLRP3 inflammasome complex and limited the mitochondrial localization of the fission protein dynamin-related protein-1 (Drp-1) triggered by IR injury. Cardioprotective effects stemming from the inhibition of sEH included preserved activities of both cytosolic thioredoxin (Trx)-1 and mitochondrial Trx-2 antioxidant enzymes. Together, these data demonstrate that inhibiting sEH imparts cardioprotection against IR injury via maintaining post-ischemic mitochondrial function and attenuating a detrimental innate inflammatory response.

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